Breastfeeding, a personalized Medicine with Influence on Short- and Long-Term Immune Health

Summary

Compared to adulthood, early postnatal life is a period that is characterized by rapid changes. The neonate’s tissues are constantly changing due to the growth process and are exposed to multiple new antigens, which are found in the environment, are present in the diet, or are associated with gut microbiota colonization (Fig. 1). The neonatal immune system has its own reactivity, which profoundly differs from that of the adult. It is neither that of a “small adult” nor is it an immature or tolerance-prone immune system. The neonatal immune system is a different one with specific requirements for activation and regulation. Breast milk is most probably a key condition for physiological (and optimal) functioning and imprinting of the immune system in early life (Fig. 1). Similar to the immune system and environment, which are constantly changing in early life, breast milk composition is constantly evolving. Volume, macronutrients, micronutrients, immunological factors, microbiota, and microbiota-shaping molecules are changing with lactation stages, and are also affected by infant growth and
environmental immune challenges [1]. Here, we will focus on factors in breast milk that we – and others – extensively studied and found to actively influence their immune trajectory and long-term immune health. More specifically, we will review the importance of TGF-β, vitamin A, immunoglobulins, and allergens in mucosal immunity in both early life and long-term allergic disease susceptibility. There is strong evidence from rodent studies and epidemiological data that oral exposure to allergens in early
life, out of the context of breast milk, is not inducing immune tolerance but, instead, is priming for allergic responses [2]. Nonbreastfed infants are exposed to only a few allergens, such as β-lactoglobulin, which occur at high concentrations. In contrast, breastfed infants are exposed to a wide variety of breast milk allergens that are found at concentrations that are at least 1 million times lower [3]. Importantly, there is evidence from rodent studies that the neonatal immune system requires very-low-dose antigen

exposure for appropriate immune reactivity. Early life is also characterized by a relative lack of TGF-β in the mucosal tissue, a physiological deficiency in vitamin A, and a low mucosal and systemic immunoglobulin secretion, which contribute to the lack of oral tolerance induction in early life in the absence of breast milk. Breast milk is providing infants with these cofac- tors, which will affect gut epithelium barrier integrity, antigen transfer, and antigen presentation for successful regulatory immune response induction [4]. This will result in a decreased risk for allergic diseases in the long term, as shown for egg allergy both in an experimental mouse model as well as in humans [5].
We are starting to decipher the specific requirements for the neonatal immune system to function optimally, and we are discovering how breast milk fulfills these requirements and guides immune trajectories from early life. Answering these questions will provide the infant with preventive and curative approaches that are tailored to this very specific period of life and will ensure long-term immune health.

References
1 Ballard O, Morrow AL: Human milk composition: nutrients and bioactive factors.
Pediatr Clin North Am 2013;60:49–74.
2 Strobel S: Immunity induced after a feed of antigen during early life: oral tolerance v.
sensitisation. Proc Nutr Soc 2001;60:437–442
3 Munblit D, Verhasselt V: Allergy prevention by breastfeeding: possible mechanisms and evidence from human cohorts. Curr Opin Allergy Clin Immunol 2016;16:427–433.
4 Turfkruyer M, Verhasselt V: Breast milk and its impact on maturation of the neonatal
immune system. Curr Opin Infect Dis 2015;28:199–206.
5 Verhasselt V, Genuneit J, Metcalfe JR, et al: Ovalbumin in breastmilk is associated with a decreased risk of IgE-mediated egg allergy in children. Allergy 2020;75:1463–1466.